Field of the Invention
The invention relates to inhibition of xanthine oxidase activity by acetic acid bacteria and their fermentation metabolites.
Background Information
Uric acid is the end product of purine metabolism in the body. A high level of uric acid in the blood leads to the formation and deposition of uric acid crystals in the joints, kidneys, and other organs. A blood uric acid concentration higher than 7 mg/dL is considered to be hyperuricemia.
Hyperuricemia is a common metabolic disorder that is associated with gout, hypertension, cardiovascular disease, diabetes, and kidney disease. An epidemiological survey performed in Taiwan from 1993 to 2008 indicated that the percentage of male and female patients demonstrating hyperuricemia was 21.6% and 9.57%, respectively.
Xanthine oxidase is a key enzyme in the synthesis of uric acid. As a result, inhibition of xanthine oxidase activity can reduce the production of uric acid. Indeed, the xanthine oxidase inhibitor, uricase, is effective for lowering the concentration of uric acid in the blood. Uricase is an enzyme not found in humans. It is typically isolated as a recombinant mammalian protein and administered by IV infusion. As such, it can be expensive to produce and difficult to administer.
Allopurinol is also a xanthine oxidase inhibitor. This compound is administered clinically to lower serum uric acid levels. However, allopurinol has side effects, such as allergic reactions, gastrointestinal discomfort, leukopenia and thrombocytopenia, hepatitis, nephropathy, and 6-mercaptopurine toxicity, which in certain cases can lead to death.
In view of the drawbacks of existing therapies for hyperuricemia, many biopharmaceutical companies focused on the development of new uric acid-lowering agents. For example, Izumida et al., J. Antibiotics 50:916-918, isolated a compound that can lower uric acid levels, namely, hydroxyakalone, from the marine bacterium Agrobacterium aurantiacum. 
Other microbial species have also been shown to possess uric-acid lowering capability, including strains of Acetobacter aceti, Acetobacter pasteurianus, Acetobacter peroxydans, Kluyveromyces fragilis, Bacillus subtilis, Lactobacillus fermentum, Lactobacillus pentosus, Lactobacillus gasseri, Lactobacillus oris, Bifidobacterium longum, and Saccharomyces cerevisiae. See, e.g., U.S. Patent Application Publications 2010/0316618, 2011/0014168, and 2013/0330299; European Patent Application Publications 2457576 and 1649863; Chinese Patent Application Publication CN102370859; and Korean Patent Application Publications KR20130099653 and KR20130004456.
The need still exists to develop new xanthine oxidase inhibitors from natural sources which can be easily produced and safely administered.